The long-term goal of this project is to obtain FDA approval to market Poloxamer-188 (P- 188) for the prevention and treatment of dilated cardiomyopathy (DCM) and heart failure (HF) in Duchenne muscular dystrophy (DMD) patients. DMD is a debilitating and fatal genetic disease, with an incidence of 1:3500 live births, characterized by a progressive loss of muscle mass and function. Approximately 20,000 boys in the US have the disease. Clinically relevant DCM is present in over 90% of DMD patients by age 18, with HF accounting for at least 20% of DMD mortality. Complications from loss of respiratory function account for 70% of fatalities, however, improvements in respiratory management including non-invasive positive pressure ventilation are lowering respiratory deaths at the expense of increasing heart related deaths. Initial studies with P-188 in the mdx mouse model of DMD demonstrated that P-188 acts to seal and repair damage to the cell membrane that result from muscle contraction. By sealing the membrane, unregulated entry of calcium ions was stopped and the heart functioned more normally. Recently, 60-day treatment, with a relatively high dose of P-188, was shown to prevent loss of heart function, stabilized heart structure and prevented cardiac muscle damage in a dog model of DMD (GRMD). These studies were all conducted with intravenous (IV) administration of P-188. If P-188 acts in DMD patients as it does in GRMD dogs, it could revolutionize the way DMD patients are managed. However, these effects need to be established at a dose that is reasonable and safe for patients and with a commercially feasible route of administration such as subcutaneous (SQ) administration. The specific aims of this proposal are to 1) Test the hypothesis that peak plasma concentrations from efficacious IV doses can be achieved by SQ dosing; and 2) To test the hypothesis that chronic SQ administration to mdx mice, can prevent remodeling and improve heart function in a dose-dependant manner. Goal of this grant application is to determine if P-188 can also prevent remodeling of the heart when dosed chronically SQ at doses that are clinically relevant in Duchenne muscular dystrophy patients. If successful, Phrixus would be able to switch development efforts, including its planned early clinical development efforts, from IV to SQ delivery. Such data, together with appropriately designed chronic GLP safety studies would support the opening of an Investigative New Drug Exemption (IND) for the chronic treatment of DMD patients. PUBLIC HEALTH RELEVANCE: Although Poloxamer-188 (P-188) has been shown to be effective as a novel membrane sealant when administered intravenously (IV), a simpler route of administration such as subcutaneously (SQ) has significant advantages in terms of clinical development and commercial adoption. The goal of this Phase I proposal is to determine if P-188 can also improve heart structure and function when dosed chronically in Duchenne muscular dystrophy patients. If successful, Phrixus would be able to switch from IV to SQ delivery and greatly increase the likelihood of developing a drug capable helping this patient population.